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17 Paroxysmal Movement Disorders Professor KP Bhatia Professor of Clinical Neurology, Sobell Department of Movement Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London Introduction The paroxysmal dyskinesias are a rare group of conditions manifesting as abnormal involuntary movements that recur episodically and last only a brief duration. 1 The conditions may be inherited or acquired. The abnormal movements may be choreic, dystonic, ballistic or a mixture of these.1 Between episodes, the patient is generally normal. Misdiagnosis is thus quite common. Recently many advances have taken place regarding the genetics and pathophysiological mechanisms of these conditions.2 Historical Aspects and Classification Mount and Reback first used the term paroxysmal dystonic choreoathetosis (PDC) describing episodes of “choreo-dystonia” in a 23 year old man3 lasting several hours precipitated by drinking alcohol and coffee.3,4 Other family members were similarly affected in an autosomal dominant pattern. Subsequently other families were also reported with similar descriptions.4,5 Kertesz (1967) described paroxysmal kinesigenic choreoathetosis (PKC)7 in which attacks were induced by sudden movement. It became clear that this disorder responded well to antiepileptic drugs, particularly carbamazepine.8 Lance (1977)9 classified the paroxysmal dyskinesias based primarily on duration of attacks into three types: PKC - in which there were brief attacks up to 5 minutes induced by sudden movement PDC - in which attacks were not induced by sudden movement and were of long duration up to 4 hours PED - a third form in which attacks were induced by prolonged exercise. Demerkirin and Jankovic10 more recently suggested replacing the term ‘choreoathetosis’ with dyskinesias and grouping these conditions into two broad groups namely ‘paroxysmal kinesigenic dyskinesia’ (PKD) if the disorder was induced by sudden movement and ‘paroxysmal non-kinesigenic dyskinesia’ (PKND) if it was not. These terms broadly correlate with the PKC and PDC of the Lance classification. Cases could also be described as either idiopathic (sporadic or familial) or secondary or symptomatic due to a variety of aetiologies. Clinical Features Paroxysmal Kinesigenic Dyskinesia (PKD or PKC) In this condition, brief dyskinetic episodes are precipitated by sudden movement.7 Onset is from early childhood (mean 13 years)11 with a notable predominance of males. Most cases are idiopathic and apparently sporadic. An autosomal dominant family history is present in about 23% of cases.11 The attacks usually unilateral, frequently manifest as dystonia and are induced by a sudden change in position, classically from a sitting to standing. However, even startle, continuous exercise or a sudden change in velocity can trigger them and, rarely, they can occur in sleep. A preceding ‘aura-like’ sensation in the limb which gets involved in an attack has been reported in 63% of cases with PKD. 11 Rarely the episodes can generalize. Speech can be affected but consciousness is not lost. Typically PKD attacks are very brief usually seconds to 1-2 minutes, with many attacks per day. After an attack there is usually a short refractory period. Some patients can abort an attack by stopping moving or warming up slowly. PKD patients respond dramatically to low doses of antiepileptic drugs with a particular sensitivity to carbamazepine which is the drug of choice.8,11 The attack frequency of PKD wanes over time decreasing considerably or abating in adulthood. An association with epilepsy has been recognized in some familial cases with PKD. Families with an affected with infantile convulsions with later onset of episodes of paroxysmal choreoathetosis (called infantile convulsions and choreoathetosis syndrome or ICCA syndrome) have been reported linked to the pericentromic region of chromosome 16p12-q12.12,13 Families with typical PKD with or without epilepsy have now also been linked to the same region of chromosome 16.14.16 Paroxysmal Non-Kinesigenic Dyskinesia (PNKD or PDC) Idiopathic PNKD also has its onset in childhood or adolescence with intermittent episodes of dystonia/chorea lasting many hours17 and frequently precipitated by stress, fatigue, alcohol or coffee.3 Unlike PKD the episodes are infrequent with long attack-free intervals. As with PKD more males than females are affected (1.4:1) and attacks wane with age.17 An autosomal dominant pattern of inheritance has been noted in all reported families with typical PNKD.4,18-21 A family with PDC with interictal myokymia22 and another with spasticity referred to as CSE (choreoathetosis/spasticity, episodic movement disorder) have been reported.23 Patients usually do not benefit from antiepileptic drugs like carbamazepine, although some patients may respond to levodopa.24 Two groups separately linked families with autosomal dominant PNKD to chromosome 2q and all families with typical autosomal dominant PNKD from around the world were linked to the same locus.19,20 Recently the gene for this disorder has been identified and is called the myofibrillogenesis regulator 1 gene (see genetic section). Not surprisingly, the family with the CSE syndrome has been linked to different locus on chromosome 1p but the gene is yet unknown.23 Paroxysmal Exercise-induced Dyskinesia (PED) PED is distinct from the kinesigenic form in that the attacks come on after 10-15 minutes of continuous exercise rather than at the initiation of movement.25 The attacks are usually dystonic and appear in the body part involved in the exercise, most commonly the legs, but focal jaw dystonia after chewing gum has been reported.26 It can also be triggered by cold,27 passive movements and vibration,28 and TMS.29 Linkage to the PNKD locus on chromosome 2q has been excluded in a PED family.26 However, a recessive family with rolandic epilepsy, episodic exercise-induced dystonia and writers cramp (REPED-WC syndrome) has been linked to chromosome 16p 12-11.231 in the same region of as the families with the ICCA syndrome12,13 and PKD suggesting an overlap between these disorders. Anticonvulsants are only occasionally useful in PED.25 Levodopa is sometimes beneficial as is acetazolamide and trihexiphenidyl.25 Paroxysmal Hypnogenic Dyskinesia (PHD) In this condition episodes of paroxysmal dyskinesia occur in sleep, hence the term ‘hypnogenic’. Lugaresi and Cirignotta (1981) described five patients who had attacks almost every night. 32 Typically, the patient awakes and has involuntary dystonic and ballistic thrashing movements of the limbs lasting up to 45 seconds, usually with no detectable concurrent EEG abnormalities. Several attacks can occur each night. Sporadic and familial cases have been described.33-36 This disorder was initially misdiagnosed as a type of sleep disorder.36 It is now clear that most of these cases are due to mesial frontal lobe seizures.34,35 ADNFLE (autosomal dominant nocturnal frontal lobe epilepsy) was the eponym given to describe this condition in six families in whom affected members had typical PHD attacks.35 The gene responsible for ADNFLE has been discovered in a few families (see genetics section). Antiepileptic drugs, particularly carbamazepine, are very effective in most cases.35 Pathophysiology The paroxysmal dyskinesias have many similarities to other episodic disorders of the nervous system such as episodic ataxias and periodic paralyses, suggesting a common pathophysiological mechanism.2 More and more paroxysmal neurological disorders are being discovered to be due to genetic mutations regulating ion channels called channelopathies.45-50 The periodic paralyses were found to be caused by mutations in voltage-gated sodium47 and calcium48 channels. Subsequently, the two forms of episodic ataxia (EA1 and EA2) were shown to be due to mutations of voltage-gated potassium45 and calcium channels.50 There are similarities between PKD and episodic ataxia type 1 (EA1).45 EA1 attacks are also frequently provoked by kinesigenic stimuli, similar to PKD, and episodes are also brief and frequent.51 Both conditions have an early age of onset and both have the tendency to abate in adulthood. Although EA1 typically responds to acetazolamide, like PKD, antiepileptic drugs may reduce EA1 attacks in some patients and also help the interictal myokymia seen in this disorder.51,52 Thus, like the periodic paralyses and episodic ataxias, the familial paroxysmal dyskinesias may also be due to defects in genes regulating ion channels.2 Genetics (Table 1) Paroxysmal Non-kinesigenic Dyskinesia (PNKD) Two separate groups reported linkage to microsatellite markers on distal 2q (2q31-q36).20,21 This was further confirmed in a British family,53 a North American family of German descent and a Japanese family, all with typical PNKD with autosmal dominant inhertitance.53-55 It appears that there is genetic homogeneity for typical familial PNKD/PDC. The gene for this disorder was recently identified and is called the myofibrillogenesis regulator 1 gene.56 Mis-sense mutations were identified in the affected subjects from two unrelated families.57 Further confirmation was obtained in 50 individuals from eight families.58 The mutations cause changes (Ala to Val) in the N-terminus of two MR-1 isoforms. The MR-1L isoform is specifically expressed in brain and is localized to the cell membrane while the MR-1S isoform is ubiquitously expressed and shows diffuse cytoplasmic and nuclear localization. Bioinformatic analysis reveals that the MR-1 gene is homologous to the hydroxyacylglutathione hydrolase (HAGH) gene. HAGH functions in a pathway to detoxify methylglyoxal, a compound present in coffee and alcoholic beverages and produced as a by-product of oxidative stress.58 These results suggest a mechanism whereby alcohol, coffee and stress may act as precipitants of attacks in PNKD.58 PKD/ ICCA syndrome/ Rolandic Epilepsy, Paroxysmal Exercise-induced Dystonia and Writers Cramp (RE-PED-WC syndrome) All three of these disorders are linked to the same pericentromic region of chromosome 16 and thus are considered together. Szepetowski and colleagues (1998) first linked four French families with what they described as the ‘ICCA syndrome’ to the pericentromeric region of chromosome 16.12 Subsequently, linkage to the same locus was further confirmed in a Chinese family said to have a similar disorder.13 Although the clinical description of the paroxysmal dyskinetic episodes in these reports was rather limited, it seemed similar to PKD. Not surprisingly, a report of eight Japanese families14 and an African-American kindred,15 all with typical PKC, were linked to the pericentromeric region of chromosome 16. Furthermore, the autosomal recessive family with rolandic epilepsy, paroxysmal exercise-induced dyskinesia and writers cramp (RE-PED-WC) syndrome has also been linked to chromosome 16 within the ICCA region.31 An Indian family with PKC has been linked to a second locus on chromosome 16q distinct from the locus of the Japanese families with PKC thus suggesting that there may be a family of genes causing paroxysmal disorders on the pericentromic region of chromosome 16.16 Different candidate genes including ion channel genes have been excluded58 but the gene is still to be found. Furthermore, there are families with PKC which do not link to chromosome 1659 suggesting at least one more locus and confirming that PKD is genetically heterogeneous. Table 1 Mapped loci/genes for familial paroxysmal dyskinesias Condition PNKD Familial paroxysmal nonkinesigenic dyskinesia (PNKD) Paroxysmal choreoathetosis/spasticity PKD/ICCA Infantile convulsions & paroxysmal choreoathetosis (ICCA) Familial paroxysmal kinesigenic dyskinesias (PKD) PED Autosomal recessive REWC-PED syndrome HPD Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) Chromosome Gene Gene Mechanism/Channel 2q33-35 MR 1 gene Stress response pathway gene 1p Not known Not known 16p12-q12 Not known Not known 16p11.2-q12.1 Not known Not known 16p12-11.2 Not known Not known 20q13 CHRNA4 Ach receptor 15q24 ?CHRNA3 ?Ach receptor RE-WC-PED = Rolandic epilepsy, writers cramp and paroxysmal exercise-induced dystonia syndrome; Ach= Nicotinic acetylcholine receptor Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) In an Australian family, Phillips et al (1995) mapped a ADNFLE locus on chromosome 20q13.2 and the obvious candidate was the alpha 4 subunit of the neuronal acetylcholine receptor (CHRNA4) gene.60 Two different mutations (a mis-sense mutation and a 3-bp insertion) were then identified in the CHRNA4 gene in the Australian family and in a Norwegian family respectively.61,62 However, another family with ADNFLE was not linked to CHRNA4 on chromosome 20q but to a novel locus on chromosome 15q24 close to a CHRNA3/CNRNA5/CHRNB4 nicotinic acetylcholine receptor gene cluster.63 Also, in seven other families with ADNFLE and in seven sporadic cases, linkage to the ADNFLE loci on chromosome 20q13.2 and 15q24 was excluded, suggesting the existence of at least a third ADNFLE locus and supporting the fact that ADNFLE is a genetically heterogeneous disease.63 Summary The paroxysmal dyskinesias are an heterogeneous group of disorders that have the shared feature of an episodic hyperkinetic movement disorder. There are many similarities between the paroxysmal dyskinesias and other intermittent neurological disorders like periodic paralyses, episodic ataxias and migraine suggesting a common pathophysiology. It is likely that the paroxysmal dyskinesias, like these other conditions, are also caused by defective ion channel genes. The list of linked gene loci causing the paroxysmal dyskinesia phenotypes is growing rapidly (Table 1) although the genes for most of these conditions, apart from PNKD and ADNFLE, are still to be identified. Finding the genes will result in better understanding of the pathophysiology, classification and treatment of these curious disorders. References 1. Fahn S. The paroxysmal dyskinesias. In: Marsden CD, Fahn S. Movement Disorders 3, ButterworthHeinmann Ltd, Oxford 1994: 310-345. 2. Bhatia KP, Griggs RC and Ptacek LJ. Episodic movement disorders as channelopaties. Mov Disord 2000;15:429-433 3. Mount LA, Reback S. Familial paroxysmal choreoathetosis:prelimnary report of a hithero undescribed clinical syndrome. Arch Neurol Psychiatry 1940;44:841-847. 4. Forssman H. Hereditary disorder characterized by attacks of muscular contractions, induced by alcohol amongst other factors. Acta Med Scand 1961; 170: 517-33. 5. Lance JW. Sporadic and familial varieties of tonic seizures. J Neurol Neurosurg Psychiatry 1963;26: 519. 6. Smith LA, Heersema PH. Periodic dystonia. Mayo Clin Proc 1941;16:842-846 7. Kertesz A. Paroxysmal kinesigenic choreoathetosis. An entity within the paroxysmal choreoathetosis syndrome. Description of 10 cases, including 1 autopsied. Neurology 1967;17:680-690. 8. Kato M and Araki S. Paroxysmal kinesigenic choreoathetosis. Report of a case relieved by carbamazepine. Arch Neurol 1969;20:508-13. 9. Lance JW. Familial paroxysmal dystonic choreoathetosis and its differentiation from related syndromes. Ann Neurol 1977; 2: 285-93. 10. Demirkirin M, Jankovic J. Paroxysmal dyskinesias: clinical features and classification. Ann Neurol 1995;38:571-579. 11. Houser MK, Soland VL, Bhatia KP, Quinn NP and Marsden CD Paroxysmal kinesigenic choreoathetosis: a report of 26 cases. J Neurol 1999; 246: 120-6. 12. Szepetowski P, Rochette J, Berquin P, Piussan C, Lathrop GM and Monaco AP Familial infantile convulsions and paroxysmal choreoathetosis: a new neurological syndrome linked to the pericentromic region of human chromosome 16. Am J Hum Genet 1997; 61: 889-98. 13. Lee WL, Tay A, Ong HT, Goh LM, Monaco AP and Szepetowski P. Association of infantile convulsions with paroxysmal dyskinesias (ICCA syndrome): confirmaton of linkage to human chromosome 16p12-q12 in a Chinese family. Hum Genet 1998; 103: 608-12. 14. Tomita H, Nagamitsu S, Wakui K, Fukushima Y, Yamada K, Sadamatsu M et al. A gene for paroxysmal kinesigenic choreoathetosis mapped to chromosome 16p11.2-q12.1. Am J Hum Genet 1999;65:1688-97. 15. Bennett LB, Roach ES and Bowcock AM et al. A locus for paroxysmal kinesigenic dyskinesia maps to human chromosome 16. Neurology 2000; 54: 125-30. 16. Valente EM, Spacey SD, Wali GM, Bhatia KP, Dixon PH, Wood NW, Davis MB. A second paroxysmal kinesigenic choreoathetosis locus (EKD2) mapping on 16q13-q22.1 indicates a family of genes which give rise to paroxysmal disorders on human chromosome 16. Brain 2000 ;123:2040-2045. 17. Bressman SB, Fahn S, Burke RE. Paroxysmal non-kinesigenic dystonia. Adv Neurol 1988;50:403-13. 18. Richards RN and Barnett HJ. Paroxysmal dystonic choreoathetosis. A family study and review of the literature. Neurology 1968; 18: 461-9. 19. Fink JK, Rainier S, Wilkowski J, Jones SM, Kume A, Hedera P et al. Paroxysmal dystonic choreoathetosis: tight linkage to chromosome 2q. Am J Hum Genet 1996; 59:140-5. 20. Fouad GT, Servidei S, Durcan S, Bertini E and Ptacek LJ. A gene for familial dyskinesia (FPD1) maps to chromosome 2q. Am J Hum Genet 1996; 59:135-9. 21. Jarman PR, Davis MB, Hodgson SV, Marsden CD and Wood NW. Paroxysmal dystonic choreoathetosis. Genetic linkage studies in a British family. Brain 1997; 120: 2125-30. 22. Byrne E, White O and Cook M. Familial dystonic choreoathetosis with myokimia; a sleep responsive disorder. J Neurol Neurosurg Psychiatry 1991; 54: 1090-92. 23. Auburger G, ratzlaff T, Lunkes A, Nelles HW, Leube B, Binkofski F, Kugel H, et al. A gene for autososmal dominant paroxysmal choreoathetosis/spasticity (CSE) maps to the vicinity of a potassium channel gene cluster on chromososme 1p, probably within 2cM between D1S443 and D1S197. Genomics 1996;31:9094. 24. Fink JK, Hedera P, Mathay JG and Albin R. Paroxysmal dystonic choreoathetosis linked to chromosome 2q: clinical analysis and proposed pathophysiology. Neurology 1997;49:177-83. 25. Bhatia KP, Soland VL, Bhatt MH, Quinn NP, Marsden CD. Paroxysmal exercise-induced dystonia: eight new sporadic cases and a review of the literature. Mov Disord 1997;12:1007-1012. 26. Munchau A, Valente EM, Shahidi GA, Eunson LH, Hanna MG, Quinn NP, Schapira AHV, Wood NW, Bhatia KP. A new family with paroxysmal exercise -induced dystonia and migraine: a clinical and genetic study. J Neurol Neurosurg Psychiatry 2000; 68 :609-14. 27. Wali GM. Paroxysmal hemidystonia induced by prolonged exercise and cold. J Neurol Neurosurg Psychiatry 1992;55:236-7. 28. Plant GT, Williams AC, Early CJ, Marsden CD. Familial paroxysmal dystonia induced by exercise. J Neurol Neurosurg Psychiatry 1984;47:275-279. 29. Meyer B-U, Irlbacher K, Meierkord H. Analysis of stimuli triggering attacks of paroxysmal dystonia induced by exertion. J Neurol Neurosurg Psychiatry 2001;70:247-251 30. Kurlan R, Behr J, Medved L and Shoulson I . Familial paroxysmal dystonic choreoathetosis: a family study. Mov Disord 1987; 2: 187-92. 31. Guerrini R, Bonanni P, Nardocci N, Parmeggiani L, Piccirilli M, De Fusco et al. Autosomal recessive rolandic epilepsy with paroxysmal exercise-induced dystonia and writers cramp: delineation of the syndrome and gene mapping to chromosome 16p12-11.2. Ann Neurol 1999; 45: 344-52. 32. Lugaresi E and Cirignotta F. Hypnogenic paroxysmal dystonia: epileptic seizure or a new syndrome? Sleep 1981; 4: 129-38. 33. Lee BI, Lesser RP, Pippenger CE, Morris HH, Luders H, Dinner DS et al. Familial paroxysmal hypnogenic dystonia. Neurology 1985; 35: 1357-60. 34. Tinuper P, Cerullo A, Cirignotta F, Cortelli P, Lugaresi E and Montagna P . Nocturnal paroxysmal dystonia with short lasting attacks: three cases with evidence for an epileptic frontal lobe origin of seizures. Epilepsia 1990; 31: 549-56. 35. Scheffer IE, Bhatia KP, Lopes-Cendes I, Fish DR, Marsden CD, Andermann E et al. Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder. Brain 1995; 118: 61-73. 36. Scheffer IE, Bhatia KP, Lopes-Cendes I, Fish DR, Marsden CD, Andermann F et al. Autosomal dominant frontal lobe epilepsy misdiagnosed as a sleep disorder. Lancet 1994; 43: 515-7. 37. Lishman WA, Symonds CD, Whitty CW, Wilson RG. Seizures induced by movement. Brain 1962;85:93108. 38. Kinast M, Erenberg G, Rothner AD. Paroxysmal choreoathetosis, report of five cases and review of the literature. Pediatrics 1980;65:74-7. 39. Guerrini R, Sanchez-Carpintero R, Deonna T, Santucci M, Bhatia KP, Moreno T, Parmeggiani L, Bernardina BD. Early-onset absence epilepsy and paroxysmal dyskinesia. Epilepsia. 2002;43(10):1224-9. 40. Franssen H, Fortgens C, Wattendorff AE, Van Woerom TCAM. Paroxysmal kinesigenic choreoathetosis and abnormal contingent negative variation. A case report. Arch Neurol 1983;40:381-5. 41. Kim MO, Im JH, Choi CG, Lee MC. Proton MR spectroscopic findings in paroxysmal kinesigenic dyskinesia. Mov Disord 1998;13:570-575. 42. Shirane S, Sasaki M, Kogure D, Matsuda H, Hashimoto T. Increased ictal perfusion of the thalamus in paroxysmal kinesigenic dyskinesia. J Neurol Neurosurg Psychiatry. 2001 ;71:408-10. 43. Barnett MH, Jarman PR, Heales SJ, Bhatia KP. Further case of paroxysmal exercise-induced dystonia and some insights into pathogenesis.Mov Disord. 2002 ;17:1386-7. 44. Lombroso CT, Fischman A. Paroxysmal non-kinesigenic dyskinesia: pathophysiological investigations. Epileptic Disord. 1999 ;1:187-93. 45. Browne DL, Gancher ST, Nutt JG, Brunt ER, Smith EA, Kramer P, Litt M. Episodic ataxia myokimia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nature Genet 1994;8:136-140. 46. Vahedi K, Joutel A, Van Vogaert P, Ducros A, Maciazeck J, Bach JF, Bousser MG, Tournier-Lasserve. A gene for hereditary paroxysmal cerebellar ataxia maps to chromosome 19. Ann Neurol 1995;37:289-93. 47. Ptacek LJ, Tawil R, Griggs RC, Meola G, McManis P, Barohn RJ, Mendell JR, et al. Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis. Neurology 1994 ;44: 1500-1503. 48. Jurkat- Rott K, Lehmann-Horn F, Elbaz A, Heine R, Gregg RG, Hogan K, Powers PA et al. A calciumchannel mutation causing hypokalemic periodic paralysis. Hum Mol Genet 1994; 3:1415-1419 49. Kramer Pl, Yue Q, Gansher ST et al. A locus for the nystagmus-associated form of episodic ataxia maps to an 11-cm region on chromosome 19p. Am J Hum Genet 1995;57:182-185. 50. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNLIA4. Cell 1996;87:543-552. 51. Brunt ERP and Van Weerden TW . Familial paroxysmal kinesigenic ataxia and continuous myokimia. Brain 1990; 113: 1361-82. 52. Griggs RC, Moxley RT III, Lafralane RA and McQuillen J. Hereditary paroxysmal ataxia, response to acetazolamide. Neurology 1978; 28: 1259-64. 53. Raskind WH, Bolin T, Wolff J, Fink J, Matsushita M, Litt M et al. Further localization of a gene for paroxysmal dystonic choreoathetosis to a 5-cM region on chromosome 2q34. Hum Genet 1998; 102: 93-7. 54. Hofele K, Benecke R and Auburger G. Gene locus FPD1 of the dystonic Mount-Reback type of autosomaldominant paroxysmal choreoathetosis. Neurology 1997; 49: 1252-7. 55. Matsuo H, Kamakura K, Saito M, Okano M, Nagase T, Tadano Y et al. Familial paroxysmal dystonic choreoathetosis: clinical findings in a large Japanese family and genetic linkage to 2q. Arch Neurol 1999; 56: 721-6. 56. Rainier S, Thomas D, Tokarz D, Ming L, Bui M, Plein E, Zhao X, Lemons R, Albin R, Delaney C, Alvarado D, Fink JK.Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis. Arch Neurol. 2004 ;61(7):1025-9. 57. Chen DH, Matsushita M, Rainier S, Meaney B, Tisch L, Feleke A, Wolff J, Lipe H, Fink J, Bird TD, Raskind WH. Presence of alanine-to-valine substitutions in myofibrillogenesis regulator 1 in paroxysmal nonkinesigenic dyskinesia: confirmation in 2 kindreds. Arch Neurol. 2005 ;62(4):597-600. 58. Lee HY, Xu Y, Huang Y, Ahn AH, Auburger GW, Pandolfo M, Kwiecinski H, Grimes DA, Lang AE, Nielsen JE, Averyanov Y, Servidei S, Friedman A, Van Bogaert P, Abramowicz MJ, Bruno MK, Sorensen BF, Tang L, Fu YH, Ptacek LJ. The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway. Hum Mol Genet. 2004 ;13(24):3161-70. 59. Spacey SD, Valente EM, Wali GM, Warner TT, Jarman PR, Schapira AH, Dixon PH, Davis MB, Bhatia KP, Wood NW. Genetic and clinical heterogeneity in paroxysmal kinesigenic dyskinesia: evidence for a third EKD gene. Mov Disord. 2002 ;17:717-25. 60. Phillips HA, Scheffer IE, Berkovic SF, Holloway VE, Sutherland GR and Mulley JC. Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q 13.2. Nat Genet 1995; 10: 117-8. 61. Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, Sutherland GR et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 1995; 11: 201-2. 62. Steinlein OK, Magnusson A, Stoodt J, Bertrand S, Weiland S, Berkovic SF et al. An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Hum Mol Genet 1997; 6: 943-7. 63. Phillips HA, Scheffer IE, Crossland KM, Bhatia KP, Fish DR, Marsden CD et al. Autosomal dominant nocturnal frontal-lobe epilepsy: genetic heterogeneity and evidence for a second locus at 15q24. Am J Hum Genet 1998; 63:1108-16.